modifying factors in striated muscle laminopathies

Conditions: Laminopathies; Emery Dreifuss Muscular Dystrophy 2; LMNA-Related Congenital Muscular Dystrophy; Dilated Cardiomyopathy-1A

Summary: mutations in the lmna gene, which codes for lamins a and c, proteins of the nuclear lamina, are responsible for a wide spectrum of pathologies, including a group specifically affecting striated skeletal and cardiac muscles, with cardiac involvement being life-threatening. at the skeletal muscle level, a wide phenotypic spectrum has been described, ranging from severe forms of congenital muscular dystrophy to less severe forms of limb-girdle muscular dystrophy. the great clinical variability of striated muscle laminopathies, both inter- and intra-familial, can be observed in the age of onset, severity of signs and progression of muscle and heart involvement. to date, more than 400 lmna mutations have been associated with striated muscle laminopathies (www.umd.be/lmna/), highlighting strong clinical and genetic heterogeneity. a few recurrent mutations linked to a difference in severity have been identified. however, these genotype-phenotype relationships and the rare cases of digenism reported do not explain all the clinical variability of laminopathies. therefore, there are probably other factors of severity than the causative mutation, called "modifier genes". identification of such modifier genes has been initiated by studying a large family with significant clinical variability in the age of onset of muscle signs. a segregation analysis within this family identified 2 potential modifier loci. high-throughput sequencing restricted to these 2 regions according to phenotypic subgroups did not led to meaningful results so far. in addition, an international retrospective study of the natural history of early muscle laminopathies has allowed the investigators to highlight a strong inter-family clinical variability in patients carrying recurrent mutations. the investigators thus have strong preliminary data that could allow them to identify modifying genetic factors in a cohort of patients carrying a mutation in the lmna gene. in order to identify these factors that modulate the clinical severity of laminopathies, the investigators wish to collect biological material (muscle and/or skin biopsies) from patients carrying a mutation in the lmna gene. the study of this biological material using multi omics technics will allow the investigators to identify and functionally validate the action of these modifying genes. omiics is a set of techniques for characterising biological molecules using high-throughput approaches such as dna sequencing, rna sequencing and/or chromatin conformation (atacseq...), proteins.


Eligibility criteria:
inclusion criteria: * patient with an lmna mutation that has led to the diagnosis of laminopathy affecting striated muscle * presenting the symptoms of the disease, whether they are index cases or related to this index case (muscle weakness, tendon retractions with or without respiratory or cardiac involvement) * have no contraindication to muscle or skin biopsy, i.e., 1) presence of a history of allergy to latex, antiseptics, local anesthetics and adhesive dressings, 2) current oral or parenteral anticoagulant therapy (anti-vitamin k, heparins, anti-platelet agents, anti-factor x, anti-thrombin), 3) history of inherited (haemophilias, platelet diseases) or acquired (vitamin k deficiency, liver failure) coagulation disorders. * patients (adult participant) or both holders of parental authority (minor participant) must sign a free and informed consent. if a minor has only 1 legal representative, the latter must attest to this on the consent form. * patients affiliated to the general french social security system, to the french universal medical coverage (cmu) or to any french equivalent scheme. exclusion criteria: * pregnant or breastfeeding women * adult subject to legal protection measures (safeguard of justice, curatorship and guardianship).

Keywords: a-type lamins lmna muscular dystrophy modifier factor